Molecular portraits of colorectal cancer morphological regions
Eva Budinská,
Martina Hrivňáková,
Tina Catela Ivkovic,
Marie Madrzyk,
Rudolf Nenutil,
Beatrix Bencsiková,
Dagmar Al Tukmachi,
Michaela Ručková,
Lenka Zdražilová Dubská,
Ondřej Slabý,
Josef Feit,
Mihnea-Paul Dragomir,
Petra Borilova Linhartova,
Sabine Tejpar,
Vlad Popovici
Affiliations
Eva Budinská
RECETOX, Faculty of Science, Masarykova Univerzita, Brno, Czech Republic
Martina Hrivňáková
RECETOX, Faculty of Science, Masarykova Univerzita, Brno, Czech Republic
Tina Catela Ivkovic
Central European Institute of Technology, Masarykova Univerzita, Brno, Czech Republic
Marie Madrzyk
Central European Institute of Technology, Masarykova Univerzita, Brno, Czech Republic
Rudolf Nenutil
Masaryk Memorial Cancer Institute, Brno, Czech Republic
Beatrix Bencsiková
Masaryk Memorial Cancer Institute, Brno, Czech Republic
Dagmar Al Tukmachi
Central European Institute of Technology, Masarykova Univerzita, Brno, Czech Republic
Michaela Ručková
Central European Institute of Technology, Masarykova Univerzita, Brno, Czech Republic
Lenka Zdražilová Dubská
Faculty of Medicine, Masarykova Univerzita, Brno, Czech Republic
Ondřej Slabý
Central European Institute of Technology, Department of Biology, Faculty of Medicine, Masarykova Univerzita, Brno, Czech Republic
Josef Feit
Department of Pharmacology and Toxicology, Faculty of Pharmacy, Masarykova Univerzita, Brno, Czech Republic
Mihnea-Paul Dragomir
Institute of Pathology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin Institute of Health, Berlin, Germany; Berlin Institute of Health, Berlin, Germany; German Cancer Research Center (DKFZ), German Cancer Consortium (DKTK), Heidelberg, Germany
Petra Borilova Linhartova
RECETOX, Faculty of Science, Masarykova Univerzita, Brno, Czech Republic
Sabine Tejpar
Faculty of Medicine, Digestive Oncology Unit, Katholieke Universiteit Leuven, Leuven, Belgium
Heterogeneity of colorectal carcinoma (CRC) represents a major hurdle towards personalized medicine. Efforts based on whole tumor profiling demonstrated that the CRC molecular subtypes were associated with specific tumor morphological patterns representing tumor subregions. We hypothesize that whole-tumor molecular descriptors depend on the morphological heterogeneity with significant impact on current molecular predictors. We investigated intra-tumor heterogeneity by morphology-guided transcriptomics to better understand the links between gene expression and tumor morphology represented by six morphological patterns (morphotypes): complex tubular, desmoplastic, mucinous, papillary, serrated, and solid/trabecular. Whole-transcriptome profiling by microarrays of 202 tumor regions (morphotypes, tumor-adjacent normal tissue, supportive stroma, and matched whole tumors) from 111 stage II-IV CRCs identified morphotype-specific gene expression profiles and molecular programs and differences in their cellular buildup. The proportion of cell types (fibroblasts, epithelial and immune cells) and differentiation of epithelial cells were the main drivers of the observed disparities with activation of EMT and TNF-α signaling in contrast to MYC and E2F targets signaling, defining major gradients of changes at molecular level. Several gene expression-based (including single-cell) classifiers, prognostic and predictive signatures were examined to study their behavior across morphotypes. Most exhibited important morphotype-dependent variability within same tumor sections, with regional predictions often contradicting the whole-tumor classification. The results show that morphotype-based tumor sampling allows the detection of molecular features that would otherwise be distilled in whole tumor profile, while maintaining histopathology context for their interpretation. This represents a practical approach at improving the reproducibility of expression profiling and, by consequence, of gene-based classifiers.